Mucin 1 (MUC1) is a membrane-bound glycoprotein that is expressed on the lumen side of epithelial cells constituting the epithelial tissues of the mammary gland, the trachea and the gastrointestinal tract, etc. (Nat. Rev. Cancer, 2004 January; 4 (1): 45-60). MUC1 is overexpressed in cancer cells of breast cancer (Mod. Pathol., 2005 October; 18 (10): 1295-304), lung cancer (Hum. Pathol., 2008 January; 39 (1): 126-36), colorectal cancer (Int. J. Oncol., 2000 January; 16 (1): 55-64), bladder cancer (PLoS One, 2014 March; 9 (3): e92742), skin cancer (Histopathology, 2000 September; 37 (3): 218-23), thyroid gland cancer (J. Pathol., 2003 July; 200 (3): 357-69), stomach cancer (J. Pathol., 2000 March; 190 (4): 437-43), pancreatic cancer (Int. J. Oncol., 2004 January; 24 (1): 107-13), kidney cancer (Mod. Pathol., 2004 February; 17 (2): 180-8), ovary cancer (Gynecol. Oncol., 2007 June; 105 (3): 695-702) and uterine cervical cancer (Am. J. Clin. Pathol., 2004 July; 122 (1): 61-9), etc. MUC1 is useful as a target molecule for detecting a cancer focus (Nat. Rev. Cancer, 2004 January; 4 (1): 45-60; and Pathol. Res. Pract., 2010 Aug. 15; 206 (8): 585-9).
MUC1 undergoes the O-glycosylation of threonine at position 9 of a 20-amino acid tandem repeat sequence HGVTSAPDTRPAPGSTAPPA (SEQ ID NO: 15) present in an extracellular domain. In cancer cells, this O-glycosylation is incomplete, and O-glycosylation such as T(Galβ1-3GalNAcα1-O-Ser/Thr), Tn(GalNAcα1-O-Ser/Thr) and 2,3ST(Neu5Acα2-3Galβ1-3GalNAcα-O-Ser/Thr) is known to occur in a cancer-specific manner (PTL 1 and NPL 1). Since MUC1 in normal tissues does not undergo such cancer-specific O-glycosylation, human cancer-specific MUC1 is particularly useful as a target molecule for treating various cancers in humans.
For example, a 1B2 antibody (PTL 1), a PankoMab antibody (NPL 2), and a 5E5 antibody (PTL 2) are known as antibodies against such human cancer-specific MUC1. Among these antibodies, the 1B2 antibody has been reported to have high specificity for human cancer-specific MUC1 as compared with the PankoMab antibody (PTL 1). It has also been reported that the dissociation constant of the 1B2 antibody is 3.7×10−10 M (PTL 1), and the dissociation constant of the 5E5 antibody is 1.7×10−9 M (NPL 1).
Meanwhile, there are also great needs for the visualization of cancer lesion. First, there are the needs for the early detection of cancer lesion. Current diagnostic modalities such as X-ray photography, echography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) cannot sensitively detect micro cancers. If micro cancers can be detected, a primary cancer can be cured by operation or radiotherapy or even a metastatic cancer is curable for a life-sustaining way by early pharmaceutical intervention. Next, there are the needs for the differentiation between a cancer lesion and a benign lesion. The current diagnostic modalities often misdiagnose a benign lesion as a cancer lesion. If differentiation can be made between a cancer lesion and a benign lesion, unnecessary biopsy can be decreased. Furthermore, there are the needs for the intraoperative visualization of cancer lesion. At present, the position or extent of a cancer lesion cannot be accurately determined during the operation of cancers including breast cancer, bladder cancer, and skin cancer. Therefore, the cancer lesion cannot be completely resected, and there is a risk of ending the operation while leaving the cancer cells. Moreover, there are the needs for the correct determination of the positions of cancer lesion. Even if postoperative recurrence and metastasis are suspected due to the elevation of a tumor marker in blood, the current diagnostic modalities cannot visualize a metastatic micro cancer. Therefore, the optimum treatment cannot be selected because whether or not the cancer has actually metastasized or which organ the cancer has metastasized to cannot be determined. Thus, it is also useful to visualize cancer lesion by molecular imaging techniques such as fluorescent imaging and γ-ray imaging (PET and SPECT) using an antibody specifically binding to human cancer-specific MUC1 as an in vivo diagnostic drug. However, any previous case using an anti-human cancer-specific MUC1 antibody as an in vivo diagnostic drug has not been known.
There is the further needs for a cancer therapeutic drug such as drug conjugated an antibody. The antibody drug is expected as a method for treating a cancer with fewer adverse reactions because of specific delivery to a cancer lesion. Radioimmunotherapy using an antibody bound to a radioisotope (Takashi Tsuruo, “Molecular Target Therapy of Cancer”, NANZANDO Co., Ltd., published on Sep. 15, 2008, p. 332-336; J. Nucl. Med., 2016 July; 57 (7): 1105-1111; and Nucl. Med. Biol., 2010 November; 37 (8): 949-955), photoimmunotherapy using an antibody bound to IRDye700DX (Nat. Med., 2011 December; 17 (12): 1685-91), and the like have been reported. IRDye700DX is a near-infrared fluorescent dye that can also be used in diagnosis. It has been reported that cell death can be induced in a cancer-specific manner through the phototoxic effect of IRDye700DX by binding this to an antibody against an antigen expressed on a cancer cell membrane, and allowing the resultant to specifically accumulate in cancer tissues, followed by irradiation with near-infrared light (Nat. Med., 2011 December; 17 (12): 1685-91). However, any previous case of clinically applying an antibody drug of an anti-human cancer-specific MUC1 antibody bound to a cancer therapeutic drug has not been known.
In general, antibodies have a long half-life in blood and require a period as long as 4 days to 5 days for reaching a tumor-to-blood ratio that confers a signal-to-background ratio sufficient for visualizing a cancer, after administration into the body (Clin. Pharmacol. Ther., 2010 May; 87 (5): 586-92). Also, the Fc regions of antibodies cause a pharmacological effect such as antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) (NPL 1; and Curr. Opin. Biotechnol., 2002 December; 13 (6): 609-14). Furthermore, antibodies highly accumulate in the liver regardless of a target, and cancer cells such as breast cancer are highly to metastasize to the liver. The accumulation in the liver interfere with the detection of hepatic metastasis at the time of diagnosis of systemic cancer lesion (Clin. Pharmacol. Ther., 2010 May; 87 (5): 586-92).
For example, low-molecular recombinant antibody fragments such as Fab, scFv, diabody, and minibody are expected to be utilized as therapeutic antibodies because of easy reaching to foci with their high tissue penetration and low cost production by using an expression system in E. coli or yeast. And also, they are reported to be utilized as diagnostic drug because of their short half-lives in blood and the feature of renal excretion (Nat. Biotechnol., 2005 September; 23 (9): 1126-36).